Abstract For patients with type 1 diabetes mellitus (T1DM), the greatest prospect for reduced morbidity and insulin independence is the replacement of [unreadable]-cells coupled with suppression of the underlying autoimmune process. Since the initially dramatic successes of islet transplantation in achieving this goal with donor islets, significant efforts have been directed at identifying and expanding alternate sources of [unreadable]-cells. These efforts have been hampered by several challenges: adult [unreadable]-cells are mainly derived by the replication of existing [unreadable]-cells, non-[unreadable]-cells give rise to [unreadable]-cells with low efficiency, and the [unreadable]-cell phenotype is difficult to achieve or maintain in vitro. In tissues that maintain mass by replication of existing cells, certain forms of injury result in the emergence of a normally quiescent progenitor cell population ("facultative stem cells"). Previous studies have pointed to the presence of such a population in the adult pancreas, but findings have been inconsistent and the precursor population has been elusive. This proposal builds on convincing recent evidence that facultative stem cells reside within the pancreatic ducts and can give rise to large numbers of [unreadable]-cells following a specific form of injury: obstruction of the pancreatic duct. This proposal seeks to identify the ductal cells that exhibit this potential, and to develop practical methods for the efficient initiation of duct-to-islet conversion in vitro or in vivo. Specifically, our goal is to stimulate duct- to-islet conversion in rodents with established diabetes as a proof-of-principle for this approach. The proposed studies have the potential for a major impact on the treatment of T1DM by promoting [unreadable]-cells neogenesis through the introduction of peptides or small molecules into the pancreatic ductal system.